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West Ashley Library
9 a.m. - 5 p.m.
Phone: (843) 766-6635
Wando Mount Pleasant Library
9 a.m. - 5 p.m.
Phone: (843) 805-6888
Village Library
9 a.m. - 1 p.m.
Phone: (843) 884-9741
St. Paul's/Hollywood Library
9 a.m. - 5 p.m.
Phone: (843) 889-3300
Otranto Road Library
9 a.m. - 5 p.m.
Phone: (843) 572-4094
Mt. Pleasant Library
9 a.m. – 5 p.m.
Phone: (843) 849-6161
McClellanville Library
9 a.m. – 1 p.m.
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Keith Summey North Charleston Library
9 a.m. - 5 p.m.
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John's Island Library
9 a.m. - 5 p.m.
Phone: (843) 559-1945
Hurd/St. Andrews Library
9 a.m. - 5 p.m.
Phone: (843) 766-2546
Folly Beach Library
9 a.m. - 2 p.m.
*open the 2nd and 4th Saturday
*open the 2nd and 4th Saturday
Phone: (843) 588-2001
Dorchester Road Library
9 a.m. - 5 p.m.
Phone: (843) 552-6466
John L. Dart Library
9 a.m. - 5 p.m.
Phone: (843) 722-7550
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9 a.m. - 5 p.m.
Phone: (843) 805-6892
Baxter-Patrick James Island
9 a.m. - 5 p.m.
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Miss Jane's Building (Edisto Library Temporary Location)
Closed
Phone: (843) 869-2355
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Phone: (843) 883-3914
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Phone: (843) 805-6930
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Defective Biomechanics and Pharmacological Rescue of Human Cardiomyocytes with Filamin C Truncations.
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- Author(s): Lazzarino, Marco; Zanetti, Michele; Chen, Suet Nee; Gao, Shanshan; Peña, Brisa; Lam, Chi Keung; Wu, Joseph C.; Taylor, Matthew R. G.; Mestroni, Luisa; Sbaizero, Orfeo
- Source:
International Journal of Molecular Sciences; Mar2024, Vol. 25 Issue 5, p2942, 18p- Subject Terms:
- Source:
- Additional Information
- Abstract: Actin-binding filamin C (FLNC) is expressed in cardiomyocytes, where it localizes to Z-discs, sarcolemma, and intercalated discs. Although FLNC truncation variants (FLNCtv) are an established cause of arrhythmias and heart failure, changes in biomechanical properties of cardiomyocytes are mostly unknown. Thus, we investigated the mechanical properties of human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) carrying FLNCtv. CRISPR/Cas9 genome-edited homozygous FLNCKO−/− hiPSC-CMs and heterozygous knock-out FLNCKO+/− hiPSC-CMs were analyzed and compared to wild-type FLNC (FLNCWT) hiPSC-CMs. Atomic force microscopy (AFM) was used to perform micro-indentation to evaluate passive and dynamic mechanical properties. A qualitative analysis of the beating traces showed gene dosage-dependent-manner "irregular" peak profiles in FLNCKO+/− and FLNCKO−/− hiPSC-CMs. Two Young's moduli were calculated: E1, reflecting the compression of the plasma membrane and actin cortex, and E2, including the whole cell with a cytoskeleton and nucleus. Both E1 and E2 showed decreased stiffness in mutant FLNCKO+/− and FLNCKO−/− iPSC-CMs compared to that in FLNCWT. The cell adhesion force and work of adhesion were assessed using the retraction curve of the SCFS. Mutant FLNC iPSC-CMs showed gene dosage-dependent decreases in the work of adhesion and adhesion forces from the heterozygous FLNCKO+/− to the FLNCKO−/− model compared to FLNCWT, suggesting damaged cytoskeleton and membrane structures. Finally, we investigated the effect of crenolanib on the mechanical properties of hiPSC-CMs. Crenolanib is an inhibitor of the Platelet-Derived Growth Factor Receptor α (PDGFRA) pathway which is upregulated in FLNCtv hiPSC-CMs. Crenolanib was able to partially rescue the stiffness of FLNCKO−/− hiPSC-CMs compared to control, supporting its potential therapeutic role. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of International Journal of Molecular Sciences is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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